Zidovudine (AZT) is an antiviral agent unable to permeate into the brain, being substrate of active efflux transport systems (AET). We have considered a new prodrug of AZT (UDCA-AZT) obtained by its ester conjugation with ursodeoxycholic acid (UDCA), a bile acid able to permeate into the central nervous system (CNS). Pharmacokinetic studies demonstrate that UDCA−AZT is quickly hydrolyzed in rat plasma and whole blood (half-life <10 s), whereas it is hydrolyzed with slower rates in human plasma (half-life = 7.53 ± 0.44 h) and whole blood (halflife = 3.71 ± 0.16 h), allowing to control the AZT release. UDCA−AZT appeared hydrolyzed also in rat brain (half-life = 7.24 ± 0.45 min) and liver homogenates (half-life = 2.70 ± 0.14 min). In the aim to study the permeation properties of the prodrug across physiological barriers between blood and brain, we have used an established human retinal pigment epithelium (HRPE) cell line to obtain a polarized cell monolayer showing epithelial features. The bidirectional permeation AZT across this monolayer was regulated by apparent permeability coefficients (PE) higher from the apical to basolateral compartments (PE = 209 ± 4 × 10−5 cm/min) than in the opposite way (PE = 133 ± 8 × 10−5 cm/min), in conformity with the in vivo behavior of AZT, actively effluxed from the CNS. The influx (PE = 39.1 ± 1.2 × 10−5 cm/min) and efflux (PE = 31.3 ± 3.6 × 10−5 cm/min) permeability coefficients of UDCA− AZT were instead the same, suggesting the ability of the prodrug to avoid the AET systems and, potentially, to allow its accumulation in the CNS.

Zidovudine (AZT) is an antiviral agent unable to permeate into the brain, being substrate of active efflux transport systems (AET). We have considered a new prodrug of AZT (UDCA-AZT) obtained by its ester conjugation with ursodeoxycholic acid (UDCA), a bile acid able to permeate into the central nervous system (CNS). Pharmacokinetic studies demonstrate that UDCA−AZT is quickly hydrolyzed in rat plasma and whole blood (half-life <10 s), whereas it is hydrolyzed with slower rates in human plasma (half-life = 7.53 ± 0.44 h) and whole blood (halflife = 3.71 ± 0.16 h), allowing to control the AZT release. UDCA−AZT appeared hydrolyzed also in rat brain (half-life = 7.24 ± 0.45 min) and liver homogenates (half-life = 2.70 ± 0.14 min). In the aim to study the permeation properties of the prodrug across physiological barriers between blood and brain, we have used an established human retinal pigment epithelium (HRPE) cell line to obtain a polarized cell monolayer showing epithelial features. The bidirectional permeation AZT across this monolayer was regulated by apparent permeability coefficients (PE) higher from the apical to basolateral compartments (PE = 209 ± 4 × 10−5 cm/min) than in the opposite way (PE = 133 ± 8 × 10−5 cm/min), in conformity with the in vivo behavior of AZT, actively effluxed from the CNS. The influx (PE = 39.1 ± 1.2 × 10−5 cm/min) and efflux (PE = 31.3 ± 3.6 × 10−5 cm/min) permeability coefficients of UDCA− AZT were instead the same, suggesting the ability of the prodrug to avoid the AET systems and, potentially, to allow its accumulation in the CNS.